Insulin processing (Homo sapiens)

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10, 13, 16, 18, 19253, 103, 103, 9, 15, 23, 2412, 14163, 83, 84, 6, 10, 11, 2852, 16, 291, 7, 10, 17, 21...3, 22, 2720secretory granulecytosolendoplasmic reticulum lumenCOPII-coated ER to Golgi transport vesicleGolgi lumen6x2xHC-INS(25-56):4xHC-INS(57-110):2xZn2+:1xCa2+Zn2+ PCSK1 Exocyst Complex2xHC-INS(25-54) TMEM27RAB27A Zn2+ EXOC2 H2OCa2+ MYO5A:MYRIP:RAB27A2xHC-INS(25-54) Ca2+ MYRIP Zn2+ EXOC7H2OSTX1A Core SNARE ComplexEXOC6 EXOC2Ca2+ PCSK2MYO5A Zn2+4xHC-INS(57-110) EXOC5 Ca2+ Ca2+ Zn2+ 6xHC-INS(25-110)Ca2+ CPE 4xHC-INS(90-110) KIF5C 6xProinsulin:2xZn2+:1xCa2+EXOC3 KIF5B CPE:Zn2+SLC30A82xHC-INS(25-56) 4xHC-INS(90-110) EXOC8 KIF5B-like proteinsVAMP2 EXOC4EXOC1 Zn2+KIF5A Zn2+ Zn2+ 6xInsulin:2xZn2+:Ca2+6xHC-INS(25-110) 6xHC-INS(25-110)EXOC52xHC-INS(25-54) 6xInsulin:2xZn2+:Ca2+ (docked granule)ERO1LB INS(25-110)SLC30A56xInsulin:2xZn2+:Ca2+ (post actin network)Ca2+ INS(57-89)6xHC-INS(25-110) 6x2xHC-INS(25-54):4xHC-INS(57-110):2xZn2+:1xCa2+EXOC32xHC-INS(25-54) INS(57-87)Zn2+ SLC30A7EXOC8Zn2+4xHC-INS(57-110) EROIL-like ProteinsERO1L EXOC4 PC1:calcium cofactorCa2+ H2OCa2+EXOC1Zn2+ SLC30A66xProinsulin:2xZn2+:1xCa2+EXOC6Zn2+EXOC7 4xHC-INS(90-110)


Description

The generation of insulin-containing secretory granules from proinsulin in the lumen of the endoplasmic reticulum (ER) can be described in 4 steps: formation of intramolecular disulfide bonds, formation of proinsulin-zinc-calcium complexes, proteolytic cleavage of proinsulin to yield insulin, translocation of the granules across the cytosol to the plasma membrane.
Transcription of the human insulin gene INS is activated by 4 important transcription factors: Pdx-1, MafA, Beta2/NeuroD1, and E47. The transcription factors interact with each other at the promoters of the insulin gene and act synergistically to promote transcription. Expression of the transcription factors is upregulated in response to glucose.
The preproinsulin mRNA is translated by ribosomes at the rough endoplasmic reticulum (ER) and the preproinsulin enters the secretion pathway by virtue of its signal peptide, which is cleaved during translation to yield proinsulin. Evidence indicates that the preproinsulin mRNA is stabilized by glucose.
In the process annotated in detail here, within the ER, three intramolecular disulfide bonds form between cysteine residues in the proinsulin. Formation of the bonds is the spontaneous result of the conformation of proinsulin and the oxidizing environment of the ER, which is maintained by Ero1-like alpha
The cystine bonded proinsulin then moves via vesicles from the ER to the Golgi Complex. High concentrations of zinc are maintained in the Golgi by zinc transporters ZnT5, ZnT6, and ZnT7 and the proinsulin forms complexes with zinc and calcium.
Proinsulin-zinc-calcium complexes bud in vesicles from the trans-Golgi to form immature secretory vesicles (secretory granules) in the cytosol. Within the immature granules the endoproteases Prohormone Convertase 1/3 and Prohormone Convertase 2 cleave at two sites of the proinsulin and Carboxypeptidase E removes a further 4 amino acid residues to yield the cystine-bonded A and B chains of mature insulin and the C peptide, which will also be secreted with the insulin. The insulin-zinc-calcium complexes form insoluble crystals within the granule
The insulin-containing secretory granules are then translocated across the cytosol to the inner surface of the plasma membrane. Translocation occurs initially by attachment of the granules to Kinesin-1, which motors along microtubules, and then by attachment to Myosin Va, which motors along the microfilaments of the cortical actin network.
A pancreatic beta cell contains about 10000 insulin granules of which about 1000 are docked at the plasma membrane and 50 are readily releasable in immediate response to stimulation by glucose or other secretogogues. Docking is due to interaction between the Exocyst proteins EXOC3 on the granule membrane and EXOC4 on the plasma membrane. Exocytosis is accomplished by interaction between SNARE-type proteins Syntaxin 1A and Syntaxin 4 on the plasma membrane and Synaptobrevin-2/VAMP2 on the granule membrane. Exocytosis is a calcium-dependent process due to interaction of the calcium-binding membrane protein Synaptotagmin V/IX with the SNARE-type proteins. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 264876
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: May, Bruce, Gopinathrao, G

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Bibliography

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  1. Liu M, Li Y, Cavener D, Arvan P.; ''Proinsulin disulfide maturation and misfolding in the endoplasmic reticulum.''; PubMed Europe PMC
  2. Matern HT, Yeaman C, Nelson WJ, Scheller RH.; ''The Sec6/8 complex in mammalian cells: characterization of mammalian Sec3, subunit interactions, and expression of subunits in polarized cells.''; PubMed Europe PMC
  3. Orci L, Ravazzola M, Amherdt M, Madsen O, Vassalli JD, Perrelet A.; ''Direct identification of prohormone conversion site in insulin-secreting cells.''; PubMed Europe PMC
  4. Kaarsholm NC, Ko HC, Dunn MF.; ''Comparison of solution structural flexibility and zinc binding domains for insulin, proinsulin, and miniproinsulin.''; PubMed Europe PMC
  5. Kambe T, Narita H, Yamaguchi-Iwai Y, Hirose J, Amano T, Sugiura N, Sasaki R, Mori K, Iwanaga T, Nagao M.; ''Cloning and characterization of a novel mammalian zinc transporter, zinc transporter 5, abundantly expressed in pancreatic beta cells.''; PubMed Europe PMC
  6. Dunn MF.; ''Zinc-ligand interactions modulate assembly and stability of the insulin hexamer -- a review.''; PubMed Europe PMC
  7. Qiao ZS, Min CY, Hua QX, Weiss MA, Feng YM.; ''In vitro refolding of human proinsulin. Kinetic intermediates, putative disulfide-forming pathway folding initiation site, and potential role of C-peptide in folding process.''; PubMed Europe PMC
  8. Chen H, Jawahar S, Qian Y, Duong Q, Chan G, Parker A, Meyer JM, Moore KJ, Chayen S, Gross DJ, Glaser B, Permutt MA, Fricker LD.; ''Missense polymorphism in the human carboxypeptidase E gene alters enzymatic activity.''; PubMed Europe PMC
  9. Bailyes EM, Shennan KI, Usac EF, Arden SD, Guest PC, Docherty K, Hutton JC.; ''Differences between the catalytic properties of recombinant human PC2 and endogenous rat PC2.''; PubMed Europe PMC
  10. Dodson G, Steiner D.; ''The role of assembly in insulin's biosynthesis.''; PubMed Europe PMC
  11. Kambe T, Yamaguchi-Iwai Y, Sasaki R, Nagao M.; ''Overview of mammalian zinc transporters.''; PubMed Europe PMC
  12. Chimienti F, Devergnas S, Pattou F, Schuit F, Garcia-Cuenca R, Vandewalle B, Kerr-Conte J, Van Lommel L, Grunwald D, Favier A, Seve M.; ''In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion.''; PubMed Europe PMC
  13. Poitout V, Hagman D, Stein R, Artner I, Robertson RP, Harmon JS.; ''Regulation of the insulin gene by glucose and fatty acids.''; PubMed Europe PMC
  14. Chimienti F, Favier A, Seve M.; ''ZnT-8, a pancreatic beta-cell-specific zinc transporter.''; PubMed Europe PMC
  15. Itoh Y, Tanaka S, Takekoshi S, Itoh J, Osamura RY.; ''Prohormone convertases (PC1/3 and PC2) in rat and human pancreas and islet cell tumors: subcellular immunohistochemical analysis.''; PubMed Europe PMC
  16. Rutter GA, Hill EV.; ''Insulin vesicle release: walk, kiss, pause ... then run.''; PubMed Europe PMC
  17. Min CY, Qiao ZS, Feng YM.; ''Unfolding of human proinsulin. Intermediates and possible role of its C-peptide in folding/unfolding.''; PubMed Europe PMC
  18. Bratanova-Tochkova TK, Cheng H, Daniel S, Gunawardana S, Liu YJ, Mulvaney-Musa J, Schermerhorn T, Straub SG, Yajima H, Sharp GW.; ''Triggering and augmentation mechanisms, granule pools, and biphasic insulin secretion.''; PubMed Europe PMC
  19. Gerber SH, Südhof TC.; ''Molecular determinants of regulated exocytosis.''; PubMed Europe PMC
  20. Huang L, Kirschke CP, Gitschier J.; ''Functional characterization of a novel mammalian zinc transporter, ZnT6.''; PubMed Europe PMC
  21. Liu M, Ramos-Castañeda J, Arvan P.; ''Role of the connecting peptide in insulin biosynthesis.''; PubMed Europe PMC
  22. Jackson RS, Creemers JW, Ohagi S, Raffin-Sanson ML, Sanders L, Montague CT, Hutton JC, O'Rahilly S.; ''Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene.''; PubMed Europe PMC
  23. Smeekens SP, Montag AG, Thomas G, Albiges-Rizo C, Carroll R, Benig M, Phillips LA, Martin S, Ohagi S, Gardner P.; ''Proinsulin processing by the subtilisin-related proprotein convertases furin, PC2, and PC3.''; PubMed Europe PMC
  24. Kaufmann JE, Irminger JC, Mungall J, Halban PA.; ''Proinsulin conversion in GH3 cells after coexpression of human proinsulin with the endoproteases PC2 and/or PC3.''; PubMed Europe PMC
  25. Kirschke CP, Huang L.; ''ZnT7, a novel mammalian zinc transporter, accumulates zinc in the Golgi apparatus.''; PubMed Europe PMC
  26. Chang SG, Choi KD, Jang SH, Shin HC.; ''Role of disulfide bonds in the structure and activity of human insulin.''; PubMed Europe PMC
  27. Jackson RS, Creemers JW, Farooqi IS, Raffin-Sanson ML, Varro A, Dockray GJ, Holst JJ, Brubaker PL, Corvol P, Polonsky KS, Ostrega D, Becker KL, Bertagna X, Hutton JC, White A, Dattani MT, Hussain K, Middleton SJ, Nicole TM, Milla PJ, Lindley KJ, O'Rahilly S.; ''Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency.''; PubMed Europe PMC
  28. Kadima W.; ''Role of metal ions in the T- to R-allosteric transition in the insulin hexamer.''; PubMed Europe PMC
  29. Tsuboi T, Ravier MA, Xie H, Ewart MA, Gould GW, Baldwin SA, Rutter GA.; ''Mammalian exocyst complex is required for the docking step of insulin vesicle exocytosis.''; PubMed Europe PMC

History

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CompareRevisionActionTimeUserComment
101283view11:17, 1 November 2018ReactomeTeamreactome version 66
100820view20:48, 31 October 2018ReactomeTeamreactome version 65
100361view19:23, 31 October 2018ReactomeTeamreactome version 64
99906view16:06, 31 October 2018ReactomeTeamreactome version 63
99462view14:38, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
94048view13:53, 16 August 2017ReactomeTeamreactome version 61
93674view11:30, 9 August 2017ReactomeTeamreactome version 61
87745view09:48, 25 July 2016RyanmillerOntology Term : 'classic metabolic pathway' added !
86798view09:26, 11 July 2016ReactomeTeamreactome version 56
83374view11:01, 18 November 2015ReactomeTeamVersion54
82752view14:55, 27 October 2015ReactomeTeamVersion54
82751view13:15, 27 October 2015ReactomeTeamVersion54
81765view10:10, 26 August 2015ReactomeTeamVersion53
76967view08:25, 17 July 2014ReactomeTeamFixed remaining interactions
76672view12:04, 16 July 2014ReactomeTeamFixed remaining interactions
76001view10:06, 11 June 2014ReactomeTeamRe-fixing comment source
75704view11:04, 10 June 2014ReactomeTeamReactome 48 Update
75060view13:57, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74704view08:46, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
2xHC-INS(25-54) ProteinP01308 (Uniprot-TrEMBL)
2xHC-INS(25-56) ProteinP01308 (Uniprot-TrEMBL)
4xHC-INS(57-110) ProteinP01308 (Uniprot-TrEMBL)
4xHC-INS(90-110) ProteinP01308 (Uniprot-TrEMBL)
6x2xHC-INS(25-54):4xHC-INS(57-110):2xZn2+:1xCa2+ComplexR-HSA-9023156 (Reactome)
6x2xHC-INS(25-56):4xHC-INS(57-110):2xZn2+:1xCa2+ComplexR-HSA-9023182 (Reactome)
6xHC-INS(25-110) ProteinP01308 (Uniprot-TrEMBL)
6xHC-INS(25-110)ProteinP01308 (Uniprot-TrEMBL)
6xInsulin:2xZn2+:Ca2+ (docked granule)ComplexR-HSA-386977 (Reactome)
6xInsulin:2xZn2+:Ca2+ (post actin network)ComplexR-HSA-9023192 (Reactome)
6xInsulin:2xZn2+:Ca2+ComplexR-HSA-264931 (Reactome)
6xProinsulin:2xZn2+:1xCa2+ComplexR-HSA-264908 (Reactome)
6xProinsulin:2xZn2+:1xCa2+ComplexR-HSA-265073 (Reactome)
CPE ProteinP16870 (Uniprot-TrEMBL)
CPE:Zn2+ComplexR-HSA-9023198 (Reactome)
Ca2+ MetaboliteCHEBI:29108 (ChEBI)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
Core SNARE ComplexComplexR-HSA-387383 (Reactome)
ERO1L ProteinQ96HE7 (Uniprot-TrEMBL)
ERO1LB ProteinQ86YB8 (Uniprot-TrEMBL)
EROIL-like ProteinsComplexR-HSA-4084703 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
EXOC1 ProteinQ9NV70 (Uniprot-TrEMBL)
EXOC1ProteinQ9NV70 (Uniprot-TrEMBL)
EXOC2 ProteinQ96KP1 (Uniprot-TrEMBL)
EXOC2ProteinQ96KP1 (Uniprot-TrEMBL)
EXOC3 ProteinO60645 (Uniprot-TrEMBL)
EXOC3ProteinO60645 (Uniprot-TrEMBL)
EXOC4 ProteinQ96A65 (Uniprot-TrEMBL)
EXOC4ProteinQ96A65 (Uniprot-TrEMBL)
EXOC5 ProteinO00471 (Uniprot-TrEMBL)
EXOC5ProteinO00471 (Uniprot-TrEMBL)
EXOC6 ProteinQ8TAG9 (Uniprot-TrEMBL)
EXOC6ProteinQ8TAG9 (Uniprot-TrEMBL)
EXOC7 ProteinQ9UPT5 (Uniprot-TrEMBL)
EXOC7ProteinQ9UPT5 (Uniprot-TrEMBL)
EXOC8 ProteinQ8IYI6 (Uniprot-TrEMBL)
EXOC8ProteinQ8IYI6 (Uniprot-TrEMBL)
Exocyst ComplexComplexR-HSA-264974 (Reactome)
H2OMetaboliteCHEBI:15377 (ChEBI)
INS(25-110)ProteinP01308 (Uniprot-TrEMBL)
INS(57-87)ProteinP01308 (Uniprot-TrEMBL)
INS(57-89)ProteinP01308 (Uniprot-TrEMBL)
KIF5A ProteinQ12840 (Uniprot-TrEMBL)
KIF5B ProteinP33176 (Uniprot-TrEMBL)
KIF5B-like proteinsComplexR-HSA-3878118 (Reactome) This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
KIF5C ProteinO60282 (Uniprot-TrEMBL)
MYO5A ProteinQ9Y4I1 (Uniprot-TrEMBL)
MYO5A:MYRIP:RAB27AComplexR-HSA-8931616 (Reactome)
MYRIP ProteinQ8NFW9 (Uniprot-TrEMBL)
PC1:calcium cofactorComplexR-HSA-378974 (Reactome)
PCSK1 ProteinP29120 (Uniprot-TrEMBL)
PCSK2ProteinP16519 (Uniprot-TrEMBL)
RAB27A ProteinP51159 (Uniprot-TrEMBL)
SLC30A5ProteinQ8TAD4 (Uniprot-TrEMBL)
SLC30A6ProteinQ6NXT4 (Uniprot-TrEMBL)
SLC30A7ProteinQ8NEW0 (Uniprot-TrEMBL)
SLC30A8ProteinQ8IWU4 (Uniprot-TrEMBL)
STX1A ProteinQ16623 (Uniprot-TrEMBL)
TMEM27ProteinQ9HBJ8 (Uniprot-TrEMBL)
VAMP2 ProteinP63027 (Uniprot-TrEMBL)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
Zn2+MetaboliteCHEBI:29105 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
6x2xHC-INS(25-54):4xHC-INS(57-110):2xZn2+:1xCa2+ArrowR-HSA-9023163 (Reactome)
6x2xHC-INS(25-54):4xHC-INS(57-110):2xZn2+:1xCa2+R-HSA-9023178 (Reactome)
6x2xHC-INS(25-56):4xHC-INS(57-110):2xZn2+:1xCa2+ArrowR-HSA-9023196 (Reactome)
6x2xHC-INS(25-56):4xHC-INS(57-110):2xZn2+:1xCa2+R-HSA-9023163 (Reactome)
6xHC-INS(25-110)ArrowR-HSA-264997 (Reactome)
6xHC-INS(25-110)ArrowR-HSA-265010 (Reactome)
6xHC-INS(25-110)R-HSA-264976 (Reactome)
6xHC-INS(25-110)R-HSA-265010 (Reactome)
6xInsulin:2xZn2+:Ca2+ (docked granule)ArrowR-HSA-9023173 (Reactome)
6xInsulin:2xZn2+:Ca2+ (post actin network)ArrowR-HSA-9023171 (Reactome)
6xInsulin:2xZn2+:Ca2+ (post actin network)R-HSA-9023173 (Reactome)
6xInsulin:2xZn2+:Ca2+ArrowR-HSA-265160 (Reactome)
6xInsulin:2xZn2+:Ca2+ArrowR-HSA-9023178 (Reactome)
6xInsulin:2xZn2+:Ca2+R-HSA-265160 (Reactome)
6xInsulin:2xZn2+:Ca2+R-HSA-9023171 (Reactome)
6xProinsulin:2xZn2+:1xCa2+ArrowR-HSA-264976 (Reactome)
6xProinsulin:2xZn2+:1xCa2+ArrowR-HSA-265153 (Reactome)
6xProinsulin:2xZn2+:1xCa2+R-HSA-265153 (Reactome)
6xProinsulin:2xZn2+:1xCa2+R-HSA-9023196 (Reactome)
CPE:Zn2+mim-catalysisR-HSA-9023159 (Reactome)
CPE:Zn2+mim-catalysisR-HSA-9023163 (Reactome)
Ca2+R-HSA-264976 (Reactome)
Core SNARE Complexmim-catalysisR-HSA-9023173 (Reactome)
EROIL-like Proteinsmim-catalysisR-HSA-264997 (Reactome)
EXOC1R-HSA-265177 (Reactome)
EXOC2R-HSA-265177 (Reactome)
EXOC3R-HSA-265177 (Reactome)
EXOC4R-HSA-265177 (Reactome)
EXOC5R-HSA-265177 (Reactome)
EXOC6R-HSA-265177 (Reactome)
EXOC7R-HSA-265177 (Reactome)
EXOC8R-HSA-265177 (Reactome)
Exocyst ComplexArrowR-HSA-265177 (Reactome)
H2OR-HSA-9023163 (Reactome)
H2OR-HSA-9023178 (Reactome)
H2OR-HSA-9023196 (Reactome)
INS(25-110)R-HSA-264997 (Reactome)
INS(57-87)ArrowR-HSA-9023159 (Reactome)
INS(57-89)ArrowR-HSA-9023178 (Reactome)
INS(57-89)R-HSA-9023159 (Reactome)
KIF5B-like proteinsmim-catalysisR-HSA-265160 (Reactome)
MYO5A:MYRIP:RAB27Amim-catalysisR-HSA-9023171 (Reactome)
PC1:calcium cofactormim-catalysisR-HSA-9023196 (Reactome)
PCSK2mim-catalysisR-HSA-9023178 (Reactome)
R-HSA-264976 (Reactome) In the presence of high concentrations of zinc and calcium, proinsulin spontaneously forms soluble complexes containing 6 molecules of proinsulin, 2 zinc ions, and 1 calcium ion. Zinc Transporters ZnT5, ZnT6, and ZnT7 are found in the membrane of the Golgi in pancreatic cells (and also in many other cell types). They play a role in maintaining the high zinc concentration in the Golgi lumen and thus catalyze the formation of the proinsulin-zinc-calcium complex. Other transporters, such as the newly identified ZnT9 and ZnT10, may also be involved but this is presently unknown.
R-HSA-264997 (Reactome) Cystine bonds are formed in Proinsulin-1 between cysteine residues 31 and 96, cysteine residues 43 and 109, and cysteine residues 95 and 100. Ero1-like alpha does not directly catalyze the oxidation of cysteines to cystine. Instead it maintains a suitably oxidizing environment for the reactions to occur . Though Ero1-like alpha can act via specific isomerases such as P4HB/PDI, there is currently no evidence that formation of cystine bonds in insulin requires a specific isomerase. Interestingly, even in beta cells of wild type animals, trace amounts of incorrectly bonded proinsulin can be detected. Thus, the formation of correct cystine bonds may involve a period of bond shuffling.
R-HSA-265010 (Reactome) Proinsulin in the endoplasmic reticulum moves to the Golgi apparatus via vesicles that bud from the endoplasmic reticulum.
R-HSA-265153 (Reactome) Immature, clathrin-coated vesicles containing proinsulin-zinc-calcium complexes bud from the trans-golgi network.
R-HSA-265160 (Reactome) Insulin-containing secretory vesicles are translocated along microtubules (polymerized tubulin) from the trans-golgi to the cellular cortex. Motor activity is provided by Dynamin-1 but the complex that connects the secretory granule to the Kinesin-1 is not yet fully known. The process is stimulated by intracellular calcium ions (Ca2+).
R-HSA-265177 (Reactome) A beta cell contains about 10 000 secretory granules. Of these, about 1000 are docked at the inner surface of the plasma membrane and a subset of about 100 docked granules form the "readily releasable" pool (granules which are released within about 5 minutes of glucose stimulation). As inferred from rat MIN6 cells, docking occurs by interaction between EXOC3/Sec6 located on the membrane of the secretory granule and EXOC4/Sec8 located at the plasma membrane (Tsuboi et al. 2005). Additional components (EXOC1, EXOC2, EXOC5, EXOC6, EXOC7, EXOC8) form the Exocyst Complex. EXOC7 binds the plasma membrane (Matern et al. 2001).
R-HSA-437085 (Reactome) The human gene SLC30A5 encodes the zinc transporter ZnT5. This protein is widely expressed but is most abundant in pancreatic beta cells (Kambe T et al, 2002). In these cells, ZnT5 mediates the transport of zinc into secretory granules that contain insulin.
R-HSA-437129 (Reactome) The human gene SLC30A7 encodes the zinc transporter ZnT7. It is thought to be present in the small intestine and lung in humans (Kirschke CP and Huang L, 2003). Functional properties assigned to ZnT7 are based on studies conducted with mouse experiments.
R-HSA-437136 (Reactome) The human SLC30A8 gene encodes the zinc transporter ZnT8 which is specifically expressed in pancreatic beta cells (Chimienti et al. 2005). Zinc is required for zinc-insulin crystallization within secretory vesicles of these cells. After glucose stimulation, large amounts of zinc are secreted locally in the extracellular matrix together with insulin. It has been suggested that this co-secreted zinc plays a role in islet cell paracrine and/or autocrine communication (Chimienti F et al, 2006). Loss of function mutations in SLC30A8 are strongly protective against type 2 diabetes, suggesting SLC20A8 inhibition as a therapeutic target in T2D prevention. (Flannick et al. 2014).
R-HSA-437139 (Reactome) Two human genes mediate the transport of zinc into the TGN and they are both localized to the TGN. The human gene SLC30A6 encodes the zinc transporter ZnT6. By Western blot studies, ZnT6 is only found in the brain and lung in human (Huang L et al, 2002).
R-HSA-9023159 (Reactome) Carboxypeptidase E (CPE, also called Carboxypeptidase H) cleaves the C-terminal arginine-89 and lysine-88 from the C-peptide (Chen et al. 2001 and inferred from rat Cpe). The reaction occurs in immature secretory granules (Orci et al. 1985)
Overall, proinsulin in proinsulin-zinc-calcium complexes is cleaved by endopeptidases PCSK1 (Prohormone Convertase 1/3) and PCSK2 (Prohormone Convertase 2). The exopeptidase CPE (Carboxypeptidase E, also called Carboxypeptidase H) removes 2 amino acids from the carboxyl termini of the resulting B chain (INS 25-56) and C-peptide (INS 57-87). In the major pathway of processing PCSK1 cleaves between the B chain and the C-peptide, CPE removes two arginine residues from the C-terminus of the B chain, PCSK2 cleaves between the C-peptide and the A chain (INS 90-110), and CPE removes an arginine residue and a lysine residue from the C-terminus of the C-peptide. Unlike the proinsulin-zinc calcium complex, the insulin-zinc-calcium complex is not soluble and forms crystals inside the secretory granules.
R-HSA-9023163 (Reactome) Carboxypeptidase E (CPE, also called Carboxypeptidase H) removes two arginine residues from the C-terminus of the B chain (Chen et al. 2001 and inferred from rat Cpe). The reaction occurs in immature secretory granules (Orci et al. 1985)
Overall, proinsulin in proinsulin-zinc-calcium complexes is cleaved by endopeptidases PCSK1 (Prohormone Convertase 1/3) and PCSK2 (Prohormone Convertase 2). The exopeptidase CPE (Carboxypeptidase E, also called Carboxypeptidase H) removes 2 amino acids from the carboxyl termini of the resulting B chain (INS 25-56) and C-peptide (INS 57-87). In the major pathway of processing PCSK1 cleaves between the B chain and the C-peptide, CPE removes two arginine residues from the C-terminus of the B chain, PCSK2 cleaves between the C-peptide and the A chain (INS 90-110), and CPE removes an arginine residue and a lysine residue from the C-terminus of the C-peptide. Unlike the proinsulin-zinc calcium complex, the insulin-zinc-calcium complex is not soluble and forms crystals inside the secretory granules.
R-HSA-9023171 (Reactome) Insulin-containing secretory granules are bound to Myosin Va via Rab27a in a complex of uncertain composition. Myosin Va motors along the cortical actin network (actin at the periphery of the cytoplasm), carrying the granules to the inner surface of the plasma membrane (inferred from mouse MIN6 cells).
R-HSA-9023173 (Reactome) Docking of secretory granules containing insulin occurs by interaction between EXOC3/Sec6 located on the membrane of the secretory granule and EXOC4/Sec8 located at the plasma membrane. Additional components (EXOC1, EXOC2, EXOC5, EXOC6, EXOC7, EXOC8) form the Exocyst Complex. A beta cell contains about 10 000 secretory granules. Of these, about 1000 are docked at the inner surface of the plasma membrane and a subset of about 100 docked granules form the "readily releasable" pool (granules which are released within about 5 minutes of glucose stimulation).
R-HSA-9023178 (Reactome) PCSK2 (Prohormone Convertase 2) cleaves C-terminal to arginine-89 between the C-peptide and the A-chain (INS 90-110) (Smeekens et al. 1992, Bailyes et al. 1995, Itoh et al. 1996, Kaufmann et al. 1997 and inferred from rat Pcsk2). The reaction occurs in immature secretory granules (Orci et al. 1985).
Overall, proinsulin in proinsulin-zinc-calcium complexes is cleaved by endopeptidases PCSK1 (Prohormone Convertase 1/3) and PCSK2 (Prohormone Convertase 2). The exopeptidase CPE (Carboxypeptidase E, also called Carboxypeptidase H) removes 2 amino acids from the carboxyl termini of the resulting B chain (INS 25-56) and C-peptide (INS 57-87). In the major pathway of processing PCSK1 cleaves between the B chain and the C-peptide, CPE removes two arginine residues from the C-terminus of the B chain, PCSK2 cleaves between the C-peptide and the A chain (INS 90-110), and CPE removes an arginine residue and a lysine residue from the C-terminus of the C-peptide. Unlike the proinsulin-zinc calcium complex, the insulin-zinc-calcium complex is not soluble and forms crystals inside the secretory granules.
R-HSA-9023196 (Reactome) PCSK1 cleaves C-terminal to arginine-56 in proinsulin to yield the B chain (plus two C-terminal arginine residues) and a peptide containing the C-peptide and the A chain ( Jackson et al. 2003, Jackson et al. 1997 and inferred from rat Pcsk1). The reaction occurs in immature secretory granules (Orci et al. 1985).
Overall, proinsulin in proinsulin-zinc-calcium complexes is cleaved by endopeptidases PCSK1 (Prohormone Convertase 1/3) and PCSK2 (Prohormone Convertase 2). The exopeptidase CPE (Carboxypeptidase E, also called Carboxypeptidase H) removes 2 amino acids from the carboxyl termini of the resulting B chain (INS 25-56) and C-peptide (INS 57-87). In the major pathway of processing PCSK1 cleaves between the B chain and the C-peptide, CPE removes two arginine residues from the C-terminus of the B chain, PCSK2 cleaves between the C-peptide and the A chain (INS 90-110), and CPE removes an arginine residue and a lysine residue from the C-terminus of the C-peptide. Unlike the proinsulin-zinc calcium complex, the insulin-zinc-calcium complex is not soluble and forms crystals inside the secretory granules.
SLC30A5mim-catalysisR-HSA-437085 (Reactome)
SLC30A6mim-catalysisR-HSA-437139 (Reactome)
SLC30A7mim-catalysisR-HSA-437129 (Reactome)
SLC30A8mim-catalysisR-HSA-437136 (Reactome)
TMEM27ArrowR-HSA-9023173 (Reactome)
Zn2+ArrowR-HSA-437085 (Reactome)
Zn2+ArrowR-HSA-437129 (Reactome)
Zn2+ArrowR-HSA-437136 (Reactome)
Zn2+ArrowR-HSA-437139 (Reactome)
Zn2+R-HSA-264976 (Reactome)
Zn2+R-HSA-437085 (Reactome)
Zn2+R-HSA-437129 (Reactome)
Zn2+R-HSA-437136 (Reactome)
Zn2+R-HSA-437139 (Reactome)
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